EP2385834A1 - Utilisation d'oxyde de deutérium pour le traitement d'affections virales des voies respiratoires - Google Patents

Utilisation d'oxyde de deutérium pour le traitement d'affections virales des voies respiratoires

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Publication number
EP2385834A1
EP2385834A1 EP10701904A EP10701904A EP2385834A1 EP 2385834 A1 EP2385834 A1 EP 2385834A1 EP 10701904 A EP10701904 A EP 10701904A EP 10701904 A EP10701904 A EP 10701904A EP 2385834 A1 EP2385834 A1 EP 2385834A1
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EP
European Patent Office
Prior art keywords
virus
respiratory tract
deuterium oxide
infection
oxide according
Prior art date
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Application number
EP10701904A
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German (de)
English (en)
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EP2385834B1 (fr
Inventor
Thomas Bayerl
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D2 Bioscience Group Ltd
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D2 Bioscience Group Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of deuterium dioxide (D2O) for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract.
  • D2O deuterium dioxide
  • Virus-related diseases are prevalent worldwide and pose a serious medical problem, in particular because of the high variability, adaptability and mutation rate of viruses.
  • Viruses are small particles of about 15 to 400 nm in diameter that are not present in the virus Are able to replicate themselves but need a host cell for this. According to their host specificity, viruses are distinguished that infect animals (invertebrates and vertebrates), plants, bacteria or algae, fungi and protozoa.
  • Viral infections are generally characterized by a high growth rate of the virus particles in the affected host cells, which can be described with an exponential or power law.
  • the multiplication cycle of viruses is carried out by injecting their nucleic acid (viral RNA or virus DNA) into the host cell, in which the replication of the nucleic acid takes place by utilizing the replication apparatus of the host cell.
  • nucleic acid viral RNA or virus DNA
  • the lytic cycle active infection
  • replication of the virus nucleic acid takes place in the cell nucleus of the host cell, assembly of the new virus particles in the cytoplasm, following which the host cell is finally lysed (destroyed) and the viruses are released.
  • the viruses thus released infect further host cells.
  • the nucleic acid of the virus is integrated into the genome of the host cell where it initially remains without destroying the host cell.
  • RNA viruses Due to external influences (eg UV radiation, addition of mutagenic substances), this lysogenic cycle can be transformed into a lytic cycle described above.
  • RNA viruses after their infection, a transcription of the RNA into DNA is necessary for replication by the host cell. This process occurs via reverse transcriptase, an enzyme that is encoded by virus genes and must first be synthesized in the host cell to rewrite viral RNA into viral DNA, which in turn is replicated by the DNA polymerase of the host cell.
  • Viruses are able to infect a wide range of cells, organs and hosts. Each virus species specifically infects preferred cells, such as gastric, intestinal, skin and respiratory tract cells. This leads to numerous so-called virus-based diseases.
  • Virus-based diseases of the respiratory tract represent a widespread and major pathological problem in medicine, especially for humans. With a percentage of 90%, infection by viruses is the most common cause of respiratory diseases caused by pathogens, such as viruses and bacteria.
  • Viruses causing such virus-based respiratory diseases include, but are not limited to, influenza viruses, parainfluenza viruses, respiratory syncyticaviruses, coronaviruses, rhinoviruses, coxsackieviruses, echoviruses, herpesviruses, human metapneumoviruses, and adenoviruses.
  • Affected organs are generally primarily the nose, paranasal sinuses, oral cavity, tonsils, throat, trachea, bronchi, and lungs. Depending on the type of virus and the severity of the infection, the viruses can infect localized areas of the respiratory tract or spread to multiple areas. Secondarily, the ear, especially the middle ear, and the Eustachian tube may be affected by the viral infection.
  • the viruses usually initially infect epithelial cells, such as skin, mucous and mucosal cells of the upper and / or lower respiratory tract, such as epithelial cells in the mouth, nose and throat and epithelial cells of the bronchioles, aveoli and trachea of the lungs, followed by a strong increase of the Virus in the host cell and death of the infected host cell.
  • epithelial cells such as skin, mucous and mucosal cells of the upper and / or lower respiratory tract
  • epithelial cells in the mouth, nose and throat and epithelial cells of the bronchioles, aveoli and trachea of the lungs followed by a strong increase of the Virus in the host cell and death of the infected host cell.
  • the host reacts with an immune response that leads to various symptomatic conditions.
  • the spread of rhinoviruses occurs predominantly in the epithelial cells of the mouth and nose, where it causes a local infection by cold symptoms, such as
  • Virus-based diseases of the respiratory tract include, for example, acute or chronic rhinitis (acute or chronic inflammation of the nose), paryngitis, herpangina, lateral angina, tonsilitis, laryngitis, tracheitis, acute bronchiolitis, acute bronchitis, aveolitis and pneumonia.
  • rhinitis and sinusitis (called rhinusinusitis) or laryngitis, tracheitis and bronchitis (called laryngo-tracheo-bronchitis), or the sequential occurrence (sequential occurrence) of several of these diseases is common.
  • rhinusinusitis or laryngitis, tracheitis and bronchitis
  • laryngo-tracheo-bronchitis tracheo-bronchitis
  • sequential occurrence sequential occurrence of several of these diseases
  • secondary diseases of the respiratory tract include, for example, otitis media (otitis media) and / or inflammation of the Eustachian tube, the invention also represent virus-based diseases of the respiratory tract.
  • Rhinoviruses are small, envelope-less RNA viruses from the picorna virus group, which are the upper and lower regions of the respiratory tract of the host, in particular a mammal, such as human (human pathogenic rhinoviruses or human rhinoviruses, 117 serotypes known), bovine (bovine rhinovirus ), Monkeys and ferrets, infect.
  • the replication of the human rhinoviruses occurs in the epithelial cells of the upper part of the respiratory tract, especially in the epithelial cells of the throat, mouth and nose, by binding to a cell receptor, the ICAM-1 receptor or the LDL receptor, their RNA in the Inject the host cell and then multiply through the lytic cycle.
  • the locally highly specific replication of the virus is associated with its sensitivity to low pH values, such as those found in the gastrointestinal tract, and high temperatures (temperature optimum: 32 ° C - 33 0 C) together. In regions that are further in the body, z. As the lung, the virus is due to the prevailing physiological temperature of 37 ° C only rarely and retarded replicated.
  • the diseases caused by human rhinoviruses include predominantly diseases of the upper respiratory tract, in particular rhinitis and pharyngitis, as well as acute bronchitis. These diseases often lead to secondary infections, eg. As sinusitis (sinusitis) and otitis media (infection of the middle ear). More rarely, rhinovirus infections cause lower respiratory tract disorders such as acute asthma and COPD. Rhinoviruses are the cause of about 40% - 50% of all colds and about 34% of all respiratory infectious diseases.
  • Influenza viruses are membrane-coated, RNA viruses and belong to the group of Orthomyxoviridae. They infect both mammals, especially humans, dogs, horses, pigs, etc., as well as birds. Human pathogens are the strains influenza A and influenza B. Transmission is via droplets and / or direct contact.
  • the replication of the viruses takes place in the epithelial cells of the upper and lower respiratory tract, but especially in the epithelial cells of the upper and lower trachea, the bronchi and the aveoli of the lungs. Propagation occurs via the lytic cycle.
  • Influenza viruses lead to the pathological appearance of commonly referred influenza. Mild infections induce colds, such as rhinitis and pharyngitis, accompanied by cough, chills, headache, weakness, and fever. Severe influenza infections affect not only the upper and lower parts of the respiratory tract but also cause diseases such as pharyngitis, tracheobronchitis, acute bronchitis, bronchiolitis and, more rarely and in particularly severe cases, pneumonia. Infections with Inluenza A can even be fatal.
  • Parainfluenza viruses are membrane-enveloped, medium-sized RNA viruses belonging to the
  • Group of Paramyxoviridae can be transmitted via droplets and / or direct contact.
  • they infect mammals, such as humans.
  • Human pathogenic strains containing the respiratory system of humans, especially infants, children, Immunosuppressants and the elderly infect humans are the human parainfluenza virus 1, the human influenza virus 2 and the human parainfuenza virus 3. They are also called respiroviruses.
  • Parainfluenza viruses reproduce optimally at physiological pH (pH 7.4 - pH 8) and temperatures of up to 37 ° C. They infect epithelial cells of the upper and lower respiratory tract and multiply via the lytic cycle.
  • Parainfluenza virus 1, parainfluenza virus 2 and parainfluenza virus 3 cause mild infections with cold symptoms that are similar to those of rhinitis, pharyngitis and acute bronchitis, as well as serious infections, especially laryngo-tracheo-bronchitis, tracheo-bronchitis, bronchiolitis and pneumonia. They are the main cause of laryngitis subglottica.
  • Respiratory syncytial virus is a membrane-enveloped RNA virus transmitted via droplet and / or direct infection. Both human-pathogenic and animal-pathogenic strains are known.
  • Replication of RSV initially occurs in the nasopharynx, with RSV binding to glycosaminoglycans of superficial epithelial cells and injecting its RNA into the host cell.
  • the viruses can penetrate into the lower part of the respiratory tract and multiply there, especially in the epithelial cells of the bronchioles and aveoli, through the lytic cycle.
  • Infection by RSV initially causes symptoms similar to rhinitis and pharyngitis in the upper respiratory tract, accompanied by mild fever and coughing.
  • the infestation of the lower respiratory tract is common and manifests itself in pathogenic manifestations such as tracheitis, bronchitis and bronchiolotis.
  • Rarer pathogenic manifestations are pneumonia, laryngeal diphtheria and as a secondary disease otitis media.
  • Herpesviruses are widely used in vertebrates, especially mammals, and especially in humans, horses, pigs, cattle, goats, sheep, cats and dogs.
  • Human herpesviruses (HHV) are distinguished into alpha, beta and gamma herpesviruses (HHV-1 to HHV-8), the alpha and gamma viruses being viruses that can infect animals, such as horse (equine herpesvirus), bovine (bovine herpesvirus), pig (porcines herpesvirus), cat (feline herpesvirus), dog (canine herpesvirus) and chicken (chicken herpesvirus 1).
  • Alpha herpesviruses include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella zoster virus (VZV).
  • HSV-1 herpes simplex virus 1
  • HSV-2 herpes simplex virus 2
  • VZV varicella zoster virus
  • Human alpha herpesviruses usually replicate initially in epithelial cells in the mouth and nose area.
  • the released viruses continue to infect certain nerve cells (neurons) by attaching themselves in the mouth to receptors of the nerve endings leading to the nerve nodes of the facial nerve (trigeminal nerve).
  • the viral DNA penetrates into an axon, is transported into the cytoplasm of the Nevenzellen and finally into its nucleus. There, the incorporation of virus DNA into the genome of the nerve cell and leads to a resting state (latency) in which only a few viral genes are expressed (lysogenic cycle).
  • Various external stimuli can lead to re-activation of the virus, which ultimately results in the destruction (lysis) of the nerve cell.
  • the virus progeny resulting from an activation are first transported by the axon to the site or into the area of the original infection, where they in turn infect epithelial cells.
  • HSV-1 can cause diseases of the respiratory tract, especially in the mouth. These include, for example, herpes nasalis, aphthous herpes and gigiovastitis herpetica. Furthermore, HSV infections can lead to pneumonia. Infections by coronaviruses
  • Coronaviruses are membrane-enveloped RNA viruses that infect vertebrates, particularly mammals such as humans, dogs, cats, cattle, swine, and some rodents, as well as birds. Coronaviruses are transmitted by droplet infection.
  • the human coronavirus (HCo) 229E, HCo-OC43, HCoV-NL63 and SARS infect the epithelial cells of the human respiratory tract, especially the upper respiratory tract. Propagation occurs via the lytic cycle.
  • the diseases caused by human coronaviruses include rhinitis and pharyngitis.
  • acute bronchitis, bronchiolitis, pneumonia, severe respiratory syndrome (SARS) and cervical diphteria can be induced.
  • SARS severe respiratory syndrome
  • cervical diphteria can be induced.
  • these disorders are less common.
  • Adenoviruses are DNA viruses that infect both animals and humans. Of a total of 19 species, 6 human pathogenic adenoviruses are known (human adenoviruses A to F).
  • Adenoviruses are characterized by high pH and temperature stability. They usually enter the organism via the respiratory tract. Propagation of adenoviruses is not limited locally to one area. They can infect epithelial cells of the pharynx, gastrointestinal tract and conjunctiva. They multiply via the lytic cycle.
  • infections of the respiratory tract may be caused by enteroviruses, e.g. Coxsackievirus 1, Cosackievirus 2 and Echo Viruses occur.
  • enteroviruses are very acid-stable RNA viruses, which are mainly transmitted fecal-oral and less often via droplet infections.
  • enteroviruses usually begins with an infection of the cells of the small bowel tonsils. From there, the viruses migrate via bloodstream and lymph to the target organs, e.g. the nose. Rarely enteroviruses first infect epithelial cells of the mucous membranes of the respiratory tract and from there they enter the intestine. Propagation occurs via the lytic cycle.
  • Enteroviruses may induce nonspecific, mild respiratory tract infections as well as pharyngeal tonsilitis, bronchiolitis, pneumonia, herpangina, hemorrhagic conjunctivitis and otitis media. Furthermore, infections with enteroviruses cause a variety of other systemic diseases, such as foot-and-mouth disease.
  • Alpha-sympathomimetics are alpha-adrenergic antagonists that bind to alpha-adrenoreceptors in the mucous membranes of the respiratory tract and thus have a stimulating effect on the sympathetic nervous system. By the stimulation or
  • Active ingredients are, for example, naphazoline, tetrazoline, xylometazoline, oxymetazoline and phenylephrine.
  • Antihistamines are primarily anti-inflammatory in that they inhibit or inhibit histamine receptors in the cells of the skin and mucous membranes of the respiratory tract, thereby suppressing the release of the inflammatory mediator histamine. Since the release of histamine plays a pathological role mainly in allergic reactions, antihistamines are used in particular for the treatment of allergies. However, some antihistamines, termed H1 antihistimines of the first generation, also bind to muscarinic receptors in the aforementioned
  • Mucous membranes with, as with the sympathomimetics, a stimulation of the sympathetic as a result.
  • this secondary effect leads to the swelling of the mucous membranes and to the suppression of bronchial secrecy.
  • Antihistamines can be administered both topically and orally. Examples are diphenydramine, tripolidine and chorpheniramine.
  • Immunosuppresives are pharmaceuticals that suppress the immune response of the host and thus have an anti-inflammatory effect. These include, for example, glucocorticoids, cytostatics and (chimeric) antibodies.
  • Secretolytics are substances such as salt water, chamomile and sage which are administered topically and cause the outflow of e.g. nasal secretions in rhinitis and sinusitis.
  • Propagation of the virus or "virus replication” is also the replication, as defined above, as well as beyond all processes lead to an intact virus, such as the processing of a synthesized long viral protein into smaller protein sections and the assembly of virus particles, such as the nucleocapsids to understand.
  • the aim is to intervene in the infection, replication and / or multiplication cycle of a virus by, for example, the viral infection of a host cell, the replication of the viral nucleic acid, the expression of the viral nucleic acid encoded viral proteins, the multiplication of the virus in the Host cell and / or the release of the virus from the host cell, eg by budding, inhibited or inhibited.
  • antiviral active substances also called antivirals or antivirals
  • neuramidase inhibitors such as zanamivir (Relenza®) and oseltamivir (Tamiflu®) are known.
  • the enzyme neuramidase which is inhibited by these drugs, helps newly formed viruses to bud from the host cell. After the budding, they can then infect other host cells. Inhibition of neuramidase is intended to prevent infection of other host cells (Snell NJC, New treatments for viral respiratory tract infections - opportunities and problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259; Sugrue Rl et al., Antiviral For further information, see: Control of Pandemic Influenza Virus, Ann.
  • M2 channel blockers are also known (amantadine, rimantadine). These prevent "uncoating,” ie, release of the viral nucleocapsid into the host cell cytoplasm (Snell NJC, New Treatments for Viral Respiratory Tract Infections - Opportunities and Problems, Journal of Antimicrobial Chemotherapy, 2001, Vol. 47, 251-259; Sugrue Rl et al., Antiviral Drugs, continued Control of Pandemic Influenza Virus, Annais Academy of Medicine, 2008, Vol. 37, 518-524).
  • antivirals have been developed which inhibit or inhibit enzymes such as DNA polymerase, reverse transcriptase or proteases and thus inhibit or inhibit the replication of the virus or the processing of a synthesized long viral protein into smaller sections of protein.
  • enzymes such as DNA polymerase, reverse transcriptase or proteases
  • examples of such therapeutic approaches can be found especially in the therapy of HIV infections.
  • antivirals are known which are administered systemically or topically. Examples include the active ingredients ribavirin (Flumadin®), aciclovir, valaciclovir, foscarnet and peniclovir.
  • Ribavarin is a nucleoside analogue that integrates into the RNA of the virus, thus inhibiting RNA polymerase. It comes to chain termination and thus stop the RNA replication and virus replication.
  • herpesviruses such as HSV-1, HSV-2, VZV
  • topically administered antivirals such as acyclovir, valacilovir, foscarnet and penciclovir
  • Systemic administration by systemically administering antiviral agents, a significant reduction in the activation of viruses present in host cells can be achieved, as the agents inhibit or inhibit the proliferation of the virus nucleic acid in the nucleus or the assembly of the virus particles into complete viruses in the cytoplasm of the host cells ;
  • Topical administration by topical administration of antivirals, for example via a nasal spray (aerosol) or nose drops, in the area of the respiratory tract, e.g. As the nose, a primary infection by the virus, can be hampered in an early stage, the further way of propagation of viruses, which can lead to a faster decongestion of the mucous membranes.
  • the dose required for effective treatment is relatively high and associated with severe side effects for the treated organism, e.g. Non-specific immune responses and autoimmune reactions.
  • side effects are known from the literature. Neither long-term therapy nor recurrent therapies are therefore advisable and to expect a patient;
  • Virus-based diseases of the respiratory tract can lead to further significant side effects and, for example, in the case of M2 channel blockers resistant strains of virus, which excludes a treatment of such diseases with such drugs and possibly even other drugs for future.
  • known antivirals are very specific and effective only for one or a few virus species. Since, however, no symptomatic distinction is possible with most infections of the respiratory tract, which makes it possible to differentiate between the infecting viruses, due to this high specificity of the known antivirals for many viruses no successful therapy of a virus-based disease of the respiratory tract can be guaranteed.
  • the object of the invention is therefore to provide improved antiviral agents for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract.
  • the invention relates in its first subject to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract and in its second subject the use of deuterium oxide for the manufacture of a medicament for the prophylaxis and / or treatment of virus-based diseases of the respiratory tract ,
  • a preferred embodiment of the invention relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein the virus-based diseases of the respiratory tract are acute rhinitis, chronic rhinitis, sicca rhinitis, paryngitis, herpangina, angina lateralis, tonsilitis, laryngitis, tracheitis, acute bronchiolitis, chronic bronchiolitis, acute bronchitis, chronic bronchitis, aveolitis, pneumonia, acute sinusitis, chronic sinusitis, herpetic gingivastomatitis, herpetic aphthous ulcer, herpes nasalis, adenovirus pharyngoconjunctivitis, glandular fever (infectious mononucleosis), acute asthma, chronic asthma, chronic obstructive pulmonary disease (COPD), laryngeal diphtheria, otitis media and / or Eustachian tube inflammation.
  • a preferred embodiment of the present invention therefore relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, which is a combination of two or more virus-based diseases of the respiratory tract.
  • these two or more virus-based diseases of the respiratory tract occur simultaneously or sequentially, in particular as a consequence of the first or preceding disease (s).
  • Such a combination of two or more virus-based diseases of the respiratory tract is, in a particularly preferred embodiment, rhinusinusitis, tracheobronchitis, tracheobronchiolitis, bronchopneumonia, pharyngotonsilitis and / or
  • Laryngotracheobronchitis Such a combination according to the invention can in particular also occur in an occurring rhinitis sicca and a subsequent acute rhinitis (Rhinitis acuta). Another example is acute rhinitis, followed by chronic rhinitis.
  • virus-based diseases of the respiratory tract are understood as meaning disorders of the respiratory tract which are caused by a virus through a virus infection.
  • the present invention not only discloses the therapy, but also the prophylaxis of virus-based diseases of the respiratory tract
  • virus-based diseases of the respiratory tract are therefore also to be understood as meaning those diseases of the respiratory tract which can be assigned to a prophylactic treatment of virus-based diseases of the respiratory tract within the meaning of the invention, including, for example, a virus-based disease
  • rhinitis sicca and indications derived therefrom, such as rhinitis sicca anterior, which according to the invention are therefore expressly used as a virus-based disease g of the respiratory tract.
  • a preferred use of D2O according to the invention thus relates to the administration of D2O in the event of rhinitis sicca occurring.
  • rhinitis includes all forms of rhinitis as virus-based diseases of the respiratory tract.
  • respiratory tract also called the respiratory tract or respiratory apparatus
  • the respiratory tract includes in particular the nose, paranasal sinuses, mouth, throat, larynx, trachea, tonsils, trachea, bronchus (bronchus principalis), bronchi, bronchioles, alveoli (alveoli) as well as
  • a division of the respiratory tract may further into the upper respiratory tract or upper part of the respiratory tract, in particular comprising the nose, paranasal sinuses, mouth, throat, tonsils, and the lower respiratory tract or lower respiratory tract n part of the respiratory tract, in particular comprising larynx, trachea, trachea, Stem bronchus (bronchus principalis), bronchi, bronchioles, alveoli (pulmonary alveoli), lungs.
  • D2O deuterium oxide
  • Such external administration can be achieved, for example, by aerosol, ie by nebulization and inhalation of D2O or by nebulization and spraying of the organs or areas of the organs with D2O, or by flushing the corresponding organs or areas of the organs with D2O or by administering Liquid D2O or D2O gels or D2O hydrogels are described in detail A detailed description of the routes of D2O administration according to the invention is given below.
  • Organs or regions of such organs to be defined as "externally accessible” include nose, nasal mucosa, sinus mucosa, mouth, oral mucosa, pharynx, pharynx, larynx, laryngeal mucosa, trachea, trachea, tonsils, bronchi, bronchioles, Aveoli, lungs as well as the mucosa of the trachea, trachea, tonsils, bronchi, bronchioles, aveoli and lungs.
  • viral infection in the sense of the invention means the active or passive penetration of a virus into an organism, such as plant, animal or human, and its multiplication in that organism.
  • an organism such an organism is referred to as a "host” and comprises vertebrates. especially mammals, especially humans, horses, pigs, cattle, goats, sheep, cats and dogs.
  • the cells of such a host are referred to as "host cells.”
  • an "organism to be treated” is one which either suffers from and is therapeutically treated for a virus-based respiratory disease, or for such a disease is treated prophylactically, wherein the human is a particularly preferred host.
  • An "organ to be treated” within the meaning of the invention is an organ of such an organism as defined above.
  • virus infection infection by viruses
  • viral infection infection
  • infection infection
  • viruses which cause a virus-based disease of the respiratory tract according to the invention. Some of these viruses as well as their route of infection and pathological appearance, ie the disease caused by them, have already been described in detail in the present description. It therefore relates to a preferred embodiment of the invention, the use of deuterium oxide for the prophylaxis and / or treatment of virus-based diseases of the respiratory tract, wherein the virus is a virus of the family Picornaviridae, Orthomyxoviridae, Paramyxoviriae, Coronaviridae, Adenoviridae and / or Herpesviridae is.
  • the virus is a virus of the genus Rhinovirus, Enterovirus, Influenza virus, Pneumovirus, Metapneumovirus, Coronavirus, Mastadenovirus, Simplexvirus and / or Varicellovirus. More preferably, the virus is a virus of the species Rhinivirus, Cosackievirus-1, Cosackievirus-2, Echovirus, Poliovirus, Influenza A, Influenza B, Parainfluenza, Respiratory Syncytial Virus (RSV), Human Metapneumovirus, Coronavirus, Human Adenovirus A, human adenovirus B, human adenovirus C, human adenovirus D, human adenovirus E, human adenovirus F, human herpesvirus 4 (HHV-4) (Epstein-Barr virus), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and / or varicella zoster virus (VZV).
  • HHV-4 Epstein-
  • virus type and “virus type” are used interchangeably.
  • the terms "prophylaxis and / or therapy” designate any measure suitable for the treatment of a virus-based disease of the respiratory tract, which either represents a preventive treatment of such an emerging disease or its emerging symptoms or a typical preceding disease or indication (Prophylaxis) or the treatment of the outbreak of the disease and / or the prevention of a recurrence of such a disease, for example, after a completed treatment period represents (therapy).
  • Topical or topical application or topical administration in the context of the invention means that a pharmaceutical or antiviral active ingredient, according to the invention D2O, - in contrast to the systemic absorption - not included in the bloodstream of the organism to be treated is, but only locally, in particular superficially, on / in an organ to be treated Respirationstrkates, in particular on / in the epithelial cells or mucous membranes, applied, applied or introduced, preferably in the form of drops, ie in liquid form, such as rinsing , or in gaseous form as an aerosol or vapor, or in the form of a formulation, such as a hydrogel.
  • Systemic administration in the sense of the invention means that a pharmaceutical or antiviral active substance is taken up in the bloodstream of the organism to be treated .
  • the topical administration of a pharmaceutical or antiviral drug is basically less side effects than the systemic administration, since in topical administration only locally, ie in a defined and limited area of the organ to be treated organism, high drug concentrations are achieved and not the entire organism, more precisely whose bloodstream is exposed to the drug, as is the case with systemic administration.
  • Such a pharmaceutical active substance or antiviral active substance administered topically for the prophylaxis and / or therapy of a virus-based disease of the respiratory tract should have at least one, preferably several, properties as follows:
  • deuterium oxide fulfills all of the aforementioned properties.
  • D2O has over the antiviral agents known in the prior art, in particular the antivirals, significant advantages, for example, much lower or no side effects, increased bioavailability and universal applicability to all viruses that cause infections of the respiratory tract.
  • deuterium oxide is an effective antiviral agent with potential long-term effects and is suitable for short, long-term and repeat therapies of virus-based diseases of the respiratory tract.
  • Deuterium oxide hereinafter also referred to as D2O, according to the invention is a pharmaceutical or antiviral active ingredient.
  • the term "pharmaceutical active ingredient” means any inorganic or organic molecule, substance or compound which has a pharmacological action.
  • pharmaceutically active substance is used interchangeably herein with the term “drug.”
  • Pharmaceutical agents within the meaning of the invention also include antiviral agents, including D2O.
  • antiviral agent within the meaning of the invention defines an agent which is administered for the treatment of virus-based diseases, and in particular virus-based diseases of the respiratory tract.
  • an antiviral agent is capable of already inhibiting or inhibiting the viral infection of the host cell and / or the proliferation of the viral nucleic acid in the host cell and / or the multiplication of the virus.
  • viral agent if an antiviral agent inhibits or inhibits virus replication, the term “virostatic agent” is also used.
  • the terms 'Pharmaceutical agent' and 'antiviral agent' are used synonymously within the meaning of the invention.
  • Cells in the sense of the invention are vertebrate cells, in particular mammalian cells and above all human cells (human cells), namely epithelial cells of the skin, especially skin cells, mucous cells and mucous membrane cells have been infected or infected.
  • the defined cells and host cells of the invention are those of the respiratory tract.
  • D2O D2O and its use according to the invention as antiviral agent for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract are explained below:
  • Deuterium oxide (D2O) and water (H2O) are physically different by the substitution of hydrogen atoms of H2O by deuterium atoms, with D2O having about 10% higher density and about 25% higher viscosity.
  • melting and boiling temperatures of D2O are higher than for H2O.
  • a detailed comparison of the properties is presented in Handbook of Chemistry and Physics, Section 6 (Handbook of Chemsitry and Physics, David R. Lide, Editor, 79th Edition, 1998 CRC Press, Boca Raton, USA).
  • D2O has an effect on enzymatic reactions above a certain concentration in a cell, in animal cells of more than 20 - 25%. Enzymatically controlled reactions are increasingly being altered, in particular inhibited or inhibited. One cause of this is seen in the higher bond strength of the hydrogen bonds when the hydrogen atom of the bond is substituted by a deuterium atom.
  • hydration means the addition of D 2 O molecules instead of or in addition to H 2 O molecules to a given surface, specifically the organs of the respiratory tract to be treated D20 hydration.
  • the term "degree of hydration” or “degree of hydration” is understood to mean the number of D2O molecules binding to a given surface, specifically the organs of the respiratory tract, to be treated in the time average instead of or in addition to H2O molecules.
  • Degree of hydration or degree of hydration in the sense of the invention can also be referred to as D2O degree of hydration or D2O hydration level.
  • Stability of hydration is understood here to mean the activation energy for detachment of a D 2 O or H 2 O molecule bound by hydrogen bonds from a surface, specifically the organs of the respiratory tract to be treated, a higher activation energy meaning a higher degree of sustainability Sustainability of hydration within the meaning of the invention may also be referred to as sustainability of D2O hydration.
  • Respiratory tracts are examples of particularly highly hydrated membrane surfaces, where the number of H-bond binding possibilities through the presence of Glycolipids and glycoproteins compared to other membranes (eg the skin surface) is massively increased.
  • a slight increase in hydration and / or hydration sustainability in this case has particularly significant consequences which are beneficial to the use of D2O in the present invention.
  • a cell receives different amounts of H2O depending on the degree of their respective metabolic activity.
  • a cell infected by a virus a so-called host cell, in which the virus is replicated, has a much higher metabolic activity than an uninfected cell of the same cell type of the surrounding area. The reason for this is that the host cell causes not only their own replication, but also the replication of the virus. Since increased metabolic activity of cells correlates with increased water uptake, virus-infected host cells receive significantly more water (H2O) than uninfected cells. Due to the similar physical properties of H2O and D2O, D2O is picked up by cells in parallel with H2O (when D2O and H2O are available) or instead of H2O (when only D2O is available).
  • the inhibition or inhibition of the host cell's DNA polymerase also does not replicate the viral DNA, since its replication is also affected by the involvement of the host cell. DNA polymerase takes place.
  • the enzymatic inhibition or inhibition by D2O is also carried out for synthesis of reverse transcriptase, which must first be synthesized by virus genes in the host cell to rewrite the viral RNA into viral DNA, which in turn is replicated from the DNA polymerase of the host cell. Inhibition or inhibition of certain enzymatic reactions of the host cell by D2O thus also inhibits or inhibits the replication and thus also the subsequent multiplication (as defined above) of a virus after a virus infection.
  • Another important aspect of the invention based on the described enhanced binding property of D2O is that when D2O is administered in sufficient concentration, i. more than 20%, based on the total water content of a cell, cell division is inhibited or inhibited. This is most likely, in addition to the inhibition or inhibition of DNA replication described, by the inhibition or inhibition of mitosis in the cycle of division of animal cells (Laissue JA et al., Survival of tumor-bearing mice exposed to heavy water or heavy water plus methotrexate, Cancer Research, 1982, Vol. 42, (3) 1125-1129).
  • This is according to the invention of crucial importance for the latency state in virus-based diseases of the respiratory tract, in which the viruses at rest (latency) during the lysogenic cycle described in detail above. In this state, the viral genome is integrated into the host cell genome and transferred to the host cell progeny upon division of the host cell along with the host genome. Inhibition or inhibition of cell division thus prevents transmission of the virus to new cells.
  • an inhibition or inhibition of the virus multiplication by the use of D2O is carried out for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract.
  • This inhibition or inhibition of the virus multiplication by D2O as an antiviral active ingredient takes place according to the invention in particular by The inhibition or inhibition of the replication of the virus nucleic acid and thus the multiplication of the virus and / or
  • inhibitor By the term “inhibit” according to the invention is meant that the replication of virus nucleic acids (viral DNA or viral RNA), virus proliferation and / or cell division rate of host cells of the invention slows and / or preferably up to 6%, preferably up to 10%, preferably up to 15%, also preferably up to 20%, more preferably up to 25%, more preferably up to 30%, also more preferably up to 35%, also more preferably up to 40%, also more preferably up to 45%, also more preferably up to 50%, even more preferably up to about 55%, even more preferably up to about 60%, still more preferably up to 65 %, also more preferably up to 70%, also more preferably up to 75%, also more preferably up to 80%, also more preferably up to 85%, even more preferably up to 90%, most preferably still up to 94% opposite the replica rate of growth or proliferation of the virus or of the rate of division of the cells without the administration of D2O.
  • virus nucleic acids viral DNA or viral RNA
  • inhibiting means that the replication of viral nucleic acids (viral DNA or viral RNA), virus proliferation and / or the cell division rate of host cells of the invention is preferably up to 95%, even more preferably up to 98%, most preferably up to 100% (and thus completely) of the rate of replication or proliferation of the virus or the rate of division of the host cell without administration of D2O.
  • viral nucleic acids viral DNA or viral RNA
  • virus proliferation and / or the cell division rate of host cells of the invention is preferably up to 95%, even more preferably up to 98%, most preferably up to 100% (and thus completely) of the rate of replication or proliferation of the virus or the rate of division of the host cell without administration of D2O.
  • D2O has considerable advantages over known antiviral and virostatic agents for the treatment of virus-based diseases of the respiratory tract, in particular by the following properties of D2O: 1) D2O is not virus-specific and can inhibit or inhibit the replication and / or multiplication of all the viruses described according to the invention. This is of particular advantage since most virus-based diseases of the respiratory tract, as described above, can be triggered by various types of viruses (including virus types) and, moreover, no symptomatic distinction is possible. Accordingly, D2O can be administered as a so-called "broad spectrum" virostatic agent for the prophylaxis and / or therapy of all virus-based diseases of the respiratory tract.
  • D2O topical administration of D2O according to the invention, e.g.
  • a sufficiently high concentration (ie, more than 20% based on the total water content of a cell) of D2O in the epithelial cells of the respiratory tract organs to be treated can be achieved without other, not virus-infected, organs of the organism are exposed to similarly high concentrations of D2O as is the case with systemic administration.
  • the D2O is obtained by direct contact of the liquid D2O or a D2O-containing formulation or a D2O-containing aerosol from the
  • D2O aerosols have a unique advantage over all other liquid aerosolizable pharmaceutical active substances. While in all other cases auxiliaries have to be added in order to transport the active pharmaceutical ingredient stably via the aerosol into the respiratory tract, this is not necessary with D2O, since it is already optimally aerosolizable as a pure molecule without additives.
  • the efficacy in the respiratory tract affecting demixing, as they occur in other mixtures (from active ingredient and excipient (s)) in the course of aerosolization can be excluded as well as by the excipients caused side effects.
  • the term "aerosolizable” or “aerosolizability” is intended to be understood as the fundamental possibility of converting a substance into an aerosol with controllable particle size by methods known from the prior art.
  • D2O has a unique advantage over all other liquid pharmaceutical agents. It can be transported like normal water (H2O) into the epithelial cells of the respiratory tract and by the strength and direction of the osmotic gradient and a manipulation of these two sizes, the penetration depth of D2O into the epithelial cells can be adapted to the therapeutic objective.
  • H2O normal water
  • the hydrogen bond strength of deuterium atoms is, as already described, higher than in the case of hydrogen atoms, in particular in the binding of water to organic molecules.
  • Topically administered D2O binds molecularly through hydrogen bonds to the next available cell surface, displacing the H2O attached there because of its higher binding strength.
  • the exchange frequency of the D20 molecules with the H2O environment is in turn somewhat slower due to this increased bond strength (and to the higher weight of the D2O molecule) than to H2O (König, S., et al., Molecular dynamics of water in oriented multilayers studied by quasi-elastic neutron scattering and deuterium NMR relaxation, 1994. J. Chem., Phys., 100, 3307-3316).
  • D2O is the only non-radioactive molecule that is very similar in properties to H2O.
  • Cells in general, and in particular the cells according to the invention can not "differentiate" between the two molecules, so that D2O is transported into the cell by active and passive transport in the same way as H2O and reaches the cell nuclei, thereby rendering cell barriers of any type , which prevent invasion of other pharmaceutical agents, also circumvent cellular mechanisms such as internalization in lysosomes or the activation of multiple drug resistance (MDR) transporters or at the organ level by the immune system, which reduce or inhibit the activity of the pharmaceutical agent D2O could be largely eliminated.
  • MDR multiple drug resistance
  • D2O as an antiviral or virostatic agent is the fact that concentrations of less than 20% D2O (based on the total water content of the cell) do not show any significant effects in the cell and therefore normal cells, which because of their active, virus-infected cells lower water permeability and / or water absorption record comparatively little D2O, are hardly exposed to the effects of D2O.
  • D2O is non-systemically administered according to the invention.
  • a particularly preferred embodiment of the invention is the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein deuterium oxide is administered topically.
  • Such topical administration is preferably in the form of drops, i. in liquid form, such as, for example, as a rinse, or in gaseous form as an aerosol or vapor, or in the form of a formulation, such as a hydrogel.
  • a further particularly preferred embodiment of the invention is the use of deuterium oxide, wherein the deuterium oxide hydrates the respiratory tract or the organs to be treated of the respiratory tract, in particular the mucous membranes of the respiratory tract, especially the nasal mucosa.
  • a direct administration according to the invention to virus-infected or respiratory organs to be treated, in particular the mucous membranes of the respiratory tract, such as the nasal mucosa local prophylactic or therapeutically effective D20 concentrations and a locally prophylactic or therapeutically effective hydration by D2O can be achieved and at the same time a stress on the system (ie circulation) and the side effects on healthy tissue and organs of the respiratory tract that are not to be treated, and tissues of other organs (such as the liver or kidney, which are affected by a high D2O concentration of more than 20%).
  • D2O based on the total water content of the cell
  • transport of D2O into the system can be prevented or restricted by means well known in the art.
  • these agents include targeted manipulation of the osmotic gradient across the mucosa (ie, between the systemic portion and the mucosal surface) by reducing the water potential of the administered D2O by substances suitable for altering this water potential, particularly physiologically acceptable salts such as sodium chloride , water-soluble polymers and other non-pharmaceutical substances.
  • D2O can be used alone as a pharmaceutical active substance, more precisely as an antiviral or virostatic active ingredient, or in combination with one or more further pharmaceutical active substance (s) or with one or more other non-pharmaceutical active ingredient (s) (which is particularly suitable for optimizing the topical administration of D2O as pharmaceutical agent on the mucous membranes).
  • a preferred embodiment of the present invention accordingly relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein the D2O is used in combination with at least one further pharmaceutical active ingredient and / or at least one further non-pharmaceutical active ingredient.
  • Such a combination of D2O and at least one further pharmaceutical active substance and / or at least one further non-pharmaceutical active substance is referred to below as “combination according to the invention”.
  • All uses and administrations according to the invention disclosed in this specification, for example as a formulation, liquid, hydrogel vapor or aerosol or in a solvent, topically etc. of D 2 O are likewise applicable without restriction to a combination according to the invention, unless otherwise indicated.
  • a further preferred embodiment of the present invention relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein the D2O is used in combination with at least one further pharmaceutical active substance, which is selected from the group consisting of Antivirals, sympathomimetics, in particular alpha-sympathometics, proteins, peptides, nucleic acids and immunosuppressive agents.
  • Virostatic agents are agents that inhibit the multiplication of viruses. Virostatic agents inhibit the activity of enzymes, such as DNA polymerase, reverse transcriptase or proteases, and thus inhibit or inhibit the replication of the virus or the processing of a synthesized long viral protein into smaller sections of protein. Examples include: amantadine, rimantadine.
  • Sympathomimetics are distinguished into direct and indirect sympathomimetics
  • Direct sympathomimetics activate alpha and / or beta adrenergic receptors by mimicking the effects of the physiological transmitters epinephrine and norepinephrine.
  • Direct sympathomimetics are distinguished into alpha-sympathometics and beta-sympathometics, although there are also drugs that bind to both receptors.
  • Alpha-sympathomimetics are alpha-adrenergic antagonists that are selective in alpha Bind adeno-receptors are usually used locally especially in nasal sprays to cause a narrowing of the blood vessels in the mucous membranes and a swelling of the nasal mucosa, especially in rhinitis.
  • Active substances are z, B. Naphazoline, tetryzoline, xylometazoline, oxymetazoline and phenylephrine.
  • Indirect sympathomimetics increase the concentration of physiological transmitters in the synaptic cleft. Examples are ephedrine, which causes dilation of the bronchi and stimulation of the circulation, and amphetamine and its derivatives, e.g. Methylphenidate and MDMA.
  • immunosuppressive agents such as corticosteroids and / or other or immune modulators
  • the response of the epithelial or dermal tissue to the proliferation of the viruses can be improved and optimized.
  • Proteins which can be used according to the invention are proteins which intervene in a suitable manner in the infection, replication or multiplication cycle of the virus in a host cell.
  • the proteins are the adsorption of the virus to the host cell, the injection of the virus nucleic acid into the host cell, the replication of the DNA of the host cell or the nucleic acid of the virus, the processing of the virus nucleic acid or the Assembly of the virus particles to inhibit a complete virus, preferably inhibit, or otherwise interfere in the multiplication cycle of the virus.
  • Examples include protease inhibitors, uncoating inhibitors, penetration inhibitors, reverse transcription inhibitors and DNA polymerase inhibitors.
  • Peptides which can be used according to the invention are, for example, peptides which, in a suitable manner, influence, in particular increase, the membrane permeability of the host cell membrane. As a result, an improved transport of D2O and optionally the other pharmaceutical or non-pharmaceutical agents of the invention in the Host cell can be achieved.
  • An example of this is mellitin.
  • peptides which can be used according to the invention are understood as meaning all those peptides which have effects analogous to those described above for proteins.
  • gene silencing can cause the genes involved in DNA damage defense (for example p53, BRCA1, BRCA2, ATM, CHK2) to be switched off and thus prevent the D2O in the multiplication hindered viruses in the cells in the long term (after the end of the topical administration of D2O) no longer in a latent state, but are long-term hindered in the expression of viral DNA.
  • DNA damage defense for example p53, BRCA1, BRCA2, ATM, CHK2
  • the nucleic acids are DNA, preferably oligonucleotides, sense or antisense DNA, natural or synthetic, cDNA, genomic DNA, naked DNA, single or double stranded DNA, or circular DNA, or RNA, preferably antisense RNA , RNAi, siRNA, or other RNA molecules suitable for interference that are not limited in length.
  • the concentration of the present invention used as a pharmaceutical active compound in addition D2O further pharmaceutical active substances based on the total solution of a combination according to the invention is in the range of at least 10 "8 M to at least 5 • 10 -2 M, preferably of at least 10 -7 M to 10 -3 M , most preferably from at least 10 -6 M to at least 10 -21 M.
  • a particularly preferred concentration range is in the range of at least 10 -9 M to at least 10 -2 M.
  • a likewise preferred embodiment of the present invention relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based Diseases of the respiratory tract, wherein the D2O is used in combination with at least one other non-pharmaceutical agent, wherein it is selected from the group consisting of pharmaceutically acceptable inorganic or organic acids or bases, polymers, copolymers, block copolymers, simple sugars, multiple sugars , ionic and nonionic surfactants or lipids, and mixtures thereof, albumin, transferrin and DNA repair proteins, such as kinase inhibitors.
  • non-pharmaceutical active substance in the context of the invention means any (s) pharmacologically acceptable and therapeutically useful molecule, substance or compound which is not a pharmaceutically active substance, but preferably together with at least one pharmaceutical active substance according to the invention to an organism to be treated is formulated, for example formulated in a formulation according to the invention, in order to influence, in particular to improve, qualitative properties of the active pharmaceutical ingredient (s).
  • the non-pharmaceutical active ingredients preferably do not develop any appreciable or at least no undesired pharmacological action in view of the intended prophylaxis or therapy of virus-based diseases of the respiratory tract.
  • Suitable non-pharmaceutical active ingredients are, for example, pharmacologically acceptable salts, for example sodium chloride, flavorings, vitamins, e.g. Vitamin A or Vitamin E, tocopherols or similar vitamins or provitamins occurring in the human organism, antioxidants, such as ascorbic acid, and stabilizers and / or preservatives for prolonging the use and retention of a pharmaceutical agent or formulation according to the invention and other conventional, known to those skilled non-pharmaceutical active ingredients or auxiliaries and additives.
  • pharmacologically acceptable salts for example sodium chloride
  • flavorings for example, flavorings, vitamins, e.g. Vitamin A or Vitamin E, tocopherols or similar vitamins or provitamins occurring in the human organism, antioxidants, such as ascorbic acid, and stabilizers and / or preservatives for prolonging the use and retention of a pharmaceutical agent or formulation according to the invention and other conventional, known to those skilled non-pharmaceutical active ingredients or auxiliaries and additives.
  • Water-soluble auxiliaries and additives By adding water-soluble auxiliaries and additives, such as pharmaceutically acceptable inorganic or organic acids, bases, salts and / or buffer substances for adjusting the pH, the physiological tolerability of D2O in the cells of the respiratory tract organs for non-virus-infected cells be improved.
  • water-soluble auxiliaries and additives such as pharmaceutically acceptable inorganic or organic acids, bases, salts and / or buffer substances for adjusting the pH
  • preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, with hydrochloric acid and sulfuric acid in particular being preferred.
  • organic acids are selected from the group consisting of malic acid, tartaric acid, maleic acid, succinic acid, acetic acid, formic acid and propionic acid and particularly preferably ascorbic acid, fumaric acid and citric acid.
  • carboxylic acid e.g., benzyl sulfonate
  • acetic acid e.g., benzyl sulfonate
  • formic acid and propionic acid e.g., acetic acid, formic acid and propionic acid
  • mixtures of the abovementioned acids in particular of acids which, in addition to their acidification properties, also possess other properties, for example when used as antioxidants, for example citric acid or ascorbic acid.
  • pharmaceutically acceptable bases are alkali hydroxides, alkali metal carbonates and alkali ions, preferably sodium. Mixtures of these substances can be used in particular for the adjustment and buffering of the pH, particularly preferred are potassium hydrogen phosphate and potassium potassium hydrogen phosphate.
  • Preferred buffer substances for the purposes of the invention are also PBS, HEPES, TRIS, MOPS and other physiologically acceptable buffer substances, in particular those having a pK value in the range from 4.0 to 9.0.
  • concentration of these substances is preferably in the range from micromolar to millimolar, more preferably in the range 1-100 mM.
  • water-soluble, non-cytotoxic molecules such as certain polymers (eg, but not limited to dextran, polyethylene glycol, agarose, cellulose, acrylic, hylaronic acid), copolymers and block copolymers, an additional delay (retardation ) of the D2O transition when administered topically into the epithelial cells of the respiratory tract as well as from the epithelial cells into the system (circulatory system).
  • certain polymers eg, but not limited to dextran, polyethylene glycol, agarose, cellulose, acrylic, hylaronic acid
  • copolymers and block copolymers eg, but not limited to block copolymers
  • an additional delay (retardation ) of the D2O transition when administered topically into the epithelial cells of the respiratory tract as well as from the epithelial cells into the system (circulatory system).
  • the concentration of these substances based on the total solution, is in the range of micromolar to molar, preferably in
  • the osmotic conditions in the Range of topical D2O administration as well as the D2O transport and the D2O retention in the epithelial cells of the respiratory tract are changed or optimized.
  • the concentration of these substances, based on the total solution of a combination according to the invention is preferably in the range of millimolar to molar, more preferably in the range of 1, 0 mM to 1, 5 M.
  • D 2 O By adding substances that alter the interfacial tension of D 2 O, for example, but not limited to, ionic and nonionic surfactants or
  • Lipids especially a mixture of surfactants and lipids, can transport the
  • D2O be changed when topically administered into the epithelial cells of the respiratory tract and within these epithelial cells.
  • concentration of these substances based on the total solution of a combination according to the invention, is preferably in the range from micromolar to millimolar, particularly preferably in the range 0.05-500 mM.
  • water-soluble molecules which are known to be by metabolically particularly active cells, such as.
  • virus-infected cells are taken up to a particular extent, for example albumin or transferrin
  • an additional increase in the D2O transport rate of the surrounded by a D2O hydrate shell molecules can be achieved in the target cells of the respiratory tract.
  • the concentration or dosage of D2O and optionally of the at least one further pharmaceutical and / or non-pharmaceutical active substance is subject to various factors, for example the type of treatment, type of disease, disease state of the patient (mammal), type of active substance, etc .. Dem Those skilled in such parameters are known and the determination of the specific dosages subject to the expertise of the skilled person. Suitable levels of concentration are disclosed herein. Some exemplary information on suitable concentration ranges are already listed above, and these are only intended as a guideline.
  • the D2O usable according to the invention is preferably present as a liquid.
  • the D 2 O is preferably present in a solution, preferably with H 2 O (water) as solvent, and is also referred to herein as "a mixture of D 2 O and H 2 O” or “D 2 O / H 2 O” if H 2 O is present, or as "D 2 O".
  • Pure D 2 O preferably contains D 2 O in a concentration range from 98.0 to 100%, preferably from 98.5 to 99.9%, particularly preferably 99.7%, based on the total water content of the solution.
  • a mixture of D 2 O and H 2 O according to the invention preferably contains D 2 O in a concentration range from 1 to 99%, preferably from 5 to 95%, more preferably from 10 to 90%, also preferably from 15 to 80%, more preferably from 20 to 70%, also more preferably from 30 to 60%, most preferably from 40 to 50%, these figures referring to the total water content of the mixture of D2O and H2O.
  • the preparation of a D 2 O solution according to the invention and, analogously thereto, a combination according to the invention takes place, for example, by mixing the components, in particular D 2 O and optionally H 2 O and, if appropriate, the at least one further pharmaceutical and / or non-pharmaceutical active substance.
  • a solvent may be added by mixing as described below.
  • the admixture of H 2 O or of the at least one further pharmaceutical and / or non-pharmaceutical active substance or of the solvent to D 2 O takes place in the liquid state of matter.
  • the preparation can be achieved by any suitable method.
  • D2O is used alone (ie not in combination with H2O or at least one other pharmaceutical and / or non-pharmaceutical active substance) and at a concentration of 100% and 99.9%, respectively, based on the total volume of the solution (ie pure D2O)
  • Pure D2O represents the D2O solution according to the invention.
  • the at least one further pharmaceutical active substance or other non-pharmaceutical active substance is bound to D2O.
  • "Tied" in the sense of the present invention means that the pharmaceutical or non-pharmaceutical active ingredient is hydrated by the D2O.
  • the D2O or the combination according to the invention is contained in a suitable solvent.
  • a solvent according to the invention may be an inorganic or organic solvent. Suitable solvents of the present invention should preferably be physiologically well-tolerated by the organism (especially mammal) to which the active ingredient is to be administered by solvent, i. no side effects, e.g. toxic side effects.
  • a particularly preferred solvent is distilled water. Also preferred are ethanol-water mixtures; Here, the percentage by weight of ethanol in these mixtures is preferably in the range between 5% and 99% ethanol, also preferably in the range of 10% to 96% ethanol, more preferably between 50% and 92%, most preferably between 69% and 91 % Ethanol.
  • D 2 O or a combination according to the invention or a mixture of D 2 O and H 2 O according to the invention can be present "preformulated", for example packed in suitable means for transporting pharmaceutical active substances, so-called “drug delivery” systems, for example in nanoparticles, vectors, preferably gene transfer vectors, viral or non-viral vectors, poly or lipoplex vectors, liposomes or hollow colloids (ie, hollow spheres of colloidal dimension).
  • drug delivery systems for example in nanoparticles, vectors, preferably gene transfer vectors, viral or non-viral vectors, poly or lipoplex vectors, liposomes or hollow colloids (ie, hollow spheres of colloidal dimension).
  • naked nucleic acids in particular naked DNA.
  • Suitable vectors, liposomes, hollow colloids or nanoparticles and methods for introducing substances into such vectors, liposomes, hollow colloids or nanoparticles are generally well known in the art and, for example, in Cryan SA., Carrier-based strategies for targeting protein and peptides Drugs to the Lungs, AAPS Journal, 2005, 07 (01): E20-E41 and Sambrook et al. Molecular Cloning A Laboratory Manual, Colard Spring Harbor Laboratory (1989) NY.
  • gene transfer vectors may preferably polyethylenimine or cationic lipids, such as. B DOTAP, to be used.
  • Liposomes are preferably useful for the packaging of cytostatic agents; for example, Koshkina NV et al., Koshkina, NV, et al., Paclitacel liposomes aerosol treatment induces inhibition of pulmonary metastases in murine renal carcinoma model., Clinical Cancer Research, 2001, 7, 3258-3262.
  • Proteins as pharmaceutical actives may preferably be packaged in biocompatible poly-milk / glycolic acid polymers (PLGA) by means of supercritical fluids, emulsion techniques and spray drying.
  • PLGA poly-milk / glycolic acid polymers
  • D2O is administered according to the invention preferably topically. This is done by application, application or introduction of D2O on / in the epithelial cells or mucous membranes of the respiratory tract to be treated, preferably in the form of drops, i. in liquid form, such as, for example, as a rinse, or in gaseous form as an aerosol or vapor, or in the form of a formulation, such as a hydrogel.
  • a preferred embodiment of the invention relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein the D2O is administered as an aerosol.
  • the aerosol is administered topically by being inhaled or sprayed.
  • aerosol refers to solid or liquid suspended particles with a diameter of about 0.0001 ⁇ m to about 100 ⁇ m, in gases, in particular air, the composition and form of the aerosols can vary very widely Aerosols are, for example, nucleic acids, peptides or proteins, the largest particles are, for example, mist particles Frequently, aerosols consist of mixtures of particles of different particle sizes and thereby embody a polydisperse size distribution Aerosols can be produced artificially by dispersion and condensation processes well known in the art without Propellant be used or used in conjunction with a liquefied compressed gas as a propellant gas, for example in spray cans.
  • D 2 O according to the invention preferably takes place either via a "nebuliser” or a "pump spray”.
  • a nebuliser for the present invention is any suitable for medical aerosols apparatus to understand, with the aerosol particles in the size range 50 nm to 500 microns can be produced.
  • the nebulizer sprays a defined volume of D2O, usually with the use of high pressures through small nozzles, so as to produce a sprayable on the organs to be treated of the respiratory tract, in particular on the epithelial cells and mucous membranes, especially the lower respiratory tract, applicable aerosol.
  • D2O nebulizers may be used primarily, but not limited to, for the treatment of virus-based diseases of the lower respiratory tract, such as, for example. Pharyngitis, laryngitis, bronchiolitis, bronchitis aveolitis and pneumonia.
  • Suitable nebulizers for include propellant-driven inhalers or nebulizers.
  • Propellant gases may in this case be, for example, CFCs or HFCs.
  • CFCs CFCs
  • HFCs HFCs
  • nebulizers which are suitable according to the invention are compressed-air jet nebulizers (for example PARI LC plus, PARI GmbH, Starnberg, Germany), venturi nozzle nebulizers,
  • Water-jet powered jet nebulizers or ultrasonic nebulizers e.g., AeronebLab,
  • Aerogen, Inc. Stierlin Court, Canada; eFLOW, PARI GmbH, Starnberg, Germany).
  • nebulizers of a size that can be carried by the patient e.g. the Respimat®, as described in WO 97/12687. All references cited herein are fully incorporated into the present invention.
  • a pump spray is understood to mean a medical apparatus with which larger aerosol particles with a diameter of 100 nm to 1000 ⁇ m can be produced. This is achieved by pushing the D2O out of pressure Reservoir is accelerated through a nozzle with predefined holes.
  • the aerosol particles generated with a "pump spray" are larger than those of the nebuliser, they already sediment in the mouth, throat, and nose, and the pump spray can therefore be particularly, but not limited to, administering D2O locally in the upper areas of the respiratory tract, such as the mouth, pharynx, tonsils and nose, for the treatment of virus-based diseases of the lower respiratory tract, such as rhinitis, sinusitis, tonsillitis, angina lateralis, herpangina, herpes nasalis, gingivastomatitis herpetica, and aptosis herpetica.
  • virus-based diseases of the lower respiratory tract such as rhinitis, sinusitis, tonsillitis, angina lateralis, herpangina, herpes nasalis, gingivastomatitis herpetica, and aptosis herpetica.
  • the preparation of an aerosol usable according to the invention can furthermore be carried out by means of any other suitable and known standard aerosol production techniques.
  • D2O concentrations to be used as an aerosol for the use according to the invention of D2O depend on various factors, for example the
  • an aerosol usable according to the invention contains D 2 O in a concentration range from 1 to 98% by weight, preferably from 10 to 90% by weight, also preferably from 15 to 80% by weight, more preferably from 20 to 70% by weight. also more preferably from 30 to 60% by weight, most preferably from 40 to 50% by weight.
  • a preferred embodiment of the invention relates to the use of deuterium oxide for the prophylaxis and / or therapy of virus-based diseases of the respiratory tract, wherein the D2O is administered as a formulation.
  • the formulation is administered topically by being applied to the organ of the respiratory tract to be treated, in particular to its epithelial cells or mucous membrane.
  • a formulation according to the invention is preferably a liquid or a hydrogel.
  • such a "liquid” or else liquid formulation comprises formulations of pure D 2 O, of a mixture of D 2 O and H 2 O and of a combination according to the invention, provided that the latter is in the liquid state and is preferably administered in the form of drops or as a rinse
  • Formulations according to the invention, including D2O formulations are suitable for the treatment of virus-based diseases of both the upper and the lower respiratory tract. They are applied to the organ to be treated, in particular to its epithelial cells or. Mucous membranes applied topically. For this purpose, they are preferably administered as a vapor, liquid, preferably as a rinse or drop, cream, ointment, gel or hydrogel:
  • D2O is applied as a vapor by suitable methods known in the art to the organ to be treated, in particular its epithelial cells or mucous membranes. Particularly suitable is this form of administration for the
  • D2O rinses are used to rinse the nose, mouth and throat.
  • D2O can be applied topically and in high concentrations to the organ to be treated, in particular its epithelial cells or mucous membranes.
  • D2O rinses are preferably used for the prophylaxis and / or therapy (treatment) of rhinitis, sinusitis, tonsillitis, angina lateralis, herpes nasalis, gingivitis herpetica and apthosis herpetica.
  • a D2O conditioner is particularly suitable for the treatment of rhinitis sicca.
  • D2O nasal drops may be used for the direct local administration of D2O to the organ to be treated, in particular its epithelial cells or mucous membranes such as nose and nasal mucosa, preferably for the treatment of rhinitis and sinusitis.
  • D2O nasal drops are dripped into the nose and transported by strong inhalation into upper nasal areas.
  • D2O nasal drops are particularly suitable for the treatment of rhinitis sicca.
  • D2O cream, D2O ointment, D2O gel and D2O hydrogel are applied topically to the organ to be treated, in particular its epithelial cells or mucous membranes, preferably on the mucous membranes in the mouth and nose, and in particular to
  • an “ointment” is an external pharmaceutical preparation of a basic mass lubricants, such as vaseline, to the actual pharmaceutical active ingredients, such as D2O, and / or non-pharmaceutical active ingredients are added, for example by mixing.
  • a basic mass lubricants such as vaseline
  • active ingredients such as D2O
  • non-pharmaceutical active ingredients are added, for example by mixing.
  • a cream is to be understood as meaning an ointment according to the invention which may additionally comprise further constituents, such as cosmetic active ingredients, for example fragrances, dyes and / or emulsifiers, for example lecithin.
  • cosmetic active ingredients for example fragrances, dyes and / or emulsifiers, for example lecithin.
  • a cream is also to be understood as a lotion.
  • a "gel” in the sense of the present invention is the solution of a macromolecular substance, eg agarose, acrylic acid, alginic acid, polysiloxanes or acrylamide, the concentration of which is so high that the dissolved macromolecules under suitable conditions and optionally with the addition of further Combine substances (eg salts, acids, fillers, buffer substances) into a sponge-like, three-dimensional framework containing a liquid in the cavities, which gives gels a relatively firm consistency, with a viscosity between liquid and solid, which is preferably pure D2O or a mixture of D2O and H2O according to the invention.
  • a macromolecular substance eg agarose, acrylic acid, alginic acid, polysiloxanes or acrylamide
  • a “hydrogel” refers to a gel which is characterized by a particularly high absorption capacity of water, for the purposes of the invention it preferably consists of 20-99%, more preferably 70-99%, and particularly preferably 80-99%. 99%, of water, without, however, demonstrating the theological properties of a classical liquid
  • the hydrogel is transparent transparent and at the same time spreadable without its morphology and integrity being affected by the gel spreading.
  • a formulation which can be used according to the invention in particular an ointment, cream or gel, is described by way of example in the examples. If such a formulation contains further pharmaceutical and / or non-pharmaceutical active ingredients, these are preferably added by mixing the formulation. However, it can be done by any standard method known in the art. Those skilled in such methods and also to be selected concentrations of the components or substances to be used are known.
  • concentrations of D 2 O in a formulation which can be used according to the invention are preferably in the following ranges:
  • a cream or ointment preferably in the range from 0.1 to 98% by weight, preferably from 5 to 85% by weight, also preferably from 10 to 80% by weight, particularly preferably from 15 to 70% by weight %, more preferably from 20 to 60% by weight, and most preferably from 25 to 50% by weight and
  • a gel preferably 0.1 to 99.8 wt .-%, preferably from 10 to 99 wt .-%, also preferably from 15 to 80 wt .-%, particularly preferably from 20 to 70 wt .-%, stronger preferably from 30 to 70% by weight, and most preferably from 35 to 65% by weight.
  • a formulation which can be used according to the invention also contains at least one inorganic or organic solvent.
  • the solvent is selected from the group consisting of ethanol, water and glycerol and mixtures thereof.
  • FIG. 1 shows the mean normalized concentration of HRV-39 RNA in the nasal "lavage" fluid of the prophylactic group as a function of time after the HRV-39 infection (day 0) over the period of the study for D2O nasal spray (verum) and H2O nasal spray (control) according to Example 21.
  • the first administration of the nasal spray was prior to infection with the virus.
  • FIG. 2 shows the mean "total symptom score” (TSS) after HRV-39 infection (example 21) of the prophylaxis group as a function of time after HRV-39 infection (day 0) over the period of the study for D2O nasal spray ( Verum) and H2O nasal spray (control)
  • the TSS consists of 6 individual symptoms, each of which was scored on a scale of 1-5 and then summed up, in which group the first application of the nasal spray was made before infection with the virus ,
  • Figure 3 shows the mean normalized concentration of HRV-39 RNA in the nasal "lavage" fluid of the therapy group as a function of time after HRV-39 infection (day 0) over the period of study for D2O nasal spray (verum) and H2O nasal spray (control) according to example 21.
  • the first application of the nasal spray took place 2 hours after infection with the virus.
  • FIG. 4 shows the mean total symptom score (TSS) after HRV-39 infection (example 21) of the therapy group as a function of time after HRV-39 infection (day 0) over the period of the study for D2O nasal spray ( Verum) and H2O nasal spray (control)
  • the TSS consists of 6 individual symptoms, each of which was scored on a scale of 1-5 and then summed up, in which group the first application of the nasal spray took place 2 hours after infection with the Virus.
  • FIG. 5 shows the mean normalized concentration of HRSV RNA in the nasal lavage fluid of the verum and control groups as a function of time after HRSV infection (day 0) over the period of the study for D2O aerosol (verum) and H2O aerosol (control ) according to example 22.
  • FIG. 6 shows the pulmonary function diagnostics after an HRSV infection according to Example 22 over the period of the study (7 days, infection on day 0). Shown is the "Forced Vital Volume” after 1 second exhalation (FEV1), normalized to the "Forced Vital Capacity” (FVC) in percent (FEV1 / FVC x 100) as a function of study duration.
  • the verum group received 3 doses of the D20 aerosol daily, the control group received equal administrations of the H2O aerosol.
  • Figure 7 shows Table 1, which in turn represents the number of viruses in a culture of the cell line A549 (human alveolar carcinoma basal epithelial cells) prepared according to Example 4 at the time 72 hours after infection for various viruses.
  • the number of viruses was determined by electron microscopy by counting and averaging each of 20 unlysed cells of Verumen and the control group, the protocols are described in Examples 6 to 17.
  • Figure 8 shows Table 2, which in turn indicates the number of viruses in a modified culture of the cell line A549 (human alveolar carcinoma basal epithelial cells) prepared according to Example 5 at the time 72 hours after infection for various viruses.
  • the number of viruses was determined by electron microscopy by counting and averaging each of 20 unlysed cells of the verum group and the control group.
  • Figure 9 shows Table 3, which in turn represents the results of the efficacy of D20 hydrogel (verum) and H2O hydrogel (control) for the treatment of aphthous ulcer herpetic in Example 20.
  • the total symptom score (TSS) was averaged over the number of gel applications per aphth, for "maximum size of the aphthae", “time between first symptom and first gel application”, “duration to complete complete healing", “duration to freedom from pain "was averaged over the total number of aphths treated per group (verum or control) (ie including multiple incidences), the errors given are the standard deviations.
  • FIG. 10 shows Table 4, which in turn shows the results on the effectiveness of D2O nasal spray (verum) and H2O nasal spray (control) for the prevention of rhinovirus infections after infection with the rhinovirus strain HRV-39 (Example 21).
  • TSS total symptom score
  • FIG. 11 shows Table 5, which in turn gives the results of the effectiveness of D2O
  • total 5 values 5 days total duration of the study
  • the errors given are the standard deviation.
  • the first dose of nasal spray was given 2 hours after infection with the virus.
  • Figure 12 shows Table 6, which in turn reports the efficacy of D2O aerosol (verum) and H20 aerosol (control) for the treatment of acute bronchitis due to infection by human respiratory syncytial virus (HRSV) according to example 22.
  • HRSV human respiratory syncytial virus
  • the infection was done during the day 0 of the study, the values for HRSV RNA concentration and lung function diagnostics (FEV2 / FVC) were measured on days 1-7 of the study and are reported in the table as arithmetic mean and standard deviation. The time course of both measured values is shown in FIGS. 5 and 6.
  • Example 1 Preparation of an isotonic D 2 O or H 2 O solution for rinsing, aerosolization or as a nasal spray
  • Deuterium oxide (D2O) with an enrichment of 98% or purified water (H2O) was mixed with 160 mM NaCl and adjusted to a pH of 7.0 by means of 20 mM phosphate buffer (sodium dihydrogen phosphate and di-sodium hydrogen phosphate).
  • the solutions were frozen at -70 0 C and stored until use at -20 0 C.
  • the solution was filled into standard 20 ml nasal aspirate pump spray bottles and stored in the refrigerator until protected from light.
  • Example 2 Preparation of a hydrogel based on acrylic acid It was 2.0 wt% Carbopol 980 (manufacturer: Noveon, Inc., 9911 Brecksville Rd., Cleveland, OH 44141-3247, USA) in separate batches in pure D2O (98% D enrichment), or in pure Dissolved H2O by stirring and then titrated by pipetting 10 M NaOH solution to a pH of 6.8.
  • Carbopol 980 manufactured by Noveon, Inc., 9911 Brecksville Rd., Cleveland, OH 44141-3247, USA
  • a Pari LC Plus universal nebulizer (PARI GmbH, 82319 Starnberg, Germany) was used in combination with a Pari Universal compressor which produced 200 mg / min polydisperse aerosol with an average particle size (median mass diameter) of 2.5 - 4.5 ⁇ m (operating pressure 2 , 0 bar, flow rate of the compressor air 6.0 l / min.)
  • the solutions prepared according to Example 1 were used.
  • the particle size measurement was carried out by means of dynamic light scattering in a flow cell
  • the aerosol generation was carried out at a temperature of 3O 0 C by appropriate thermostating the nebulizer in a water bath thermostat.
  • Cells of the cell line A549 (human alveolar carcinoma basal epithelial cells) of (American Type Culture Collection, Rockville, MD 1 USA) were seeded in 10 mm cell culture dishes at a cell density of 5 * 10 4 cells / cm 2 .
  • the medium used was Dulbecco's Modified Eagle Medium, DMEM, (Gibco / BRL, Life Technologies Inc, Grand Island, NY, USA) with 10% Fetal Calf Serum, FCS; (Hyclone, Logan, UT, USA), 100 U / ml penicillin, and 100 ⁇ g / ml streptomycin (Sigma Chemical Co., St. Louis, MO, USA).
  • the cells were grown to confluence at 95% humidity and 5% CO 2 .
  • the cell culture medium was changed and the new medium (DMEM with 2% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin) contained the virus in a concentration that was a multiplicity of infection (MOI) of 3 corresponded.
  • MOI multiplicity of infection
  • the probability of a cell being infected with at least one virus particle was 95% at this MOI.
  • the infection and incubation were carried out at temperature and humidity analogously as indicated above.
  • Cells of the cell line A549 (human alveolar carcinoma basal epithelial cells) of (American Type Culture Collection, Rockville, MD, USA) were seeded in 10 mm cell culture dishes at a cell density of 5 * 10 4 cells / cm 2 .
  • the medium used was Dulbecco's Modified Eagle Medium, DMEM, (Gibco / BRL, Life Technologies Inc, Grand Island, NY, USA) with 10% Fetal Calf Serum, FCS; (Hyclone, Logan, UT, USA), 100 U / ml penicillin, and 100 ⁇ g / ml streptomycin (Sigma Chemical Co., St. Louis, MO, USA).
  • the cells were grown to confluency at 95% humidity and 5% CO 2 .
  • the cell culture medium was changed and the new medium (DMEM with 2% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin diluted with 30% D2O, 98% D - Enrichment (verum culture) or diluted with 30% H2O (control culture)
  • the medium was again exchanged for a medium of identical composition containing the virus in concentrations corresponding to a multiplicity of infection of 1.
  • the infection and incubation were carried out at Temperature and humidity analogous as stated above.
  • the virus count was carried out by means of
  • Example 7 Efficacy in Rhinoviruses
  • Six cell culture dishes of type 1 cell culture according to example 4 were infected with rhinoviruses (strain RV-16 from American Type Culture Collection, Manassas, VA, USA). 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium.
  • cell culture dishes of cell culture type 1 There were 6 cell culture dishes of cell culture type 1 according to Example 4 with herpesvirus type 1, HSV-1, strain Maclntyre VR-539, American Type Culture Collection, Manassas, VA,
  • VZV Herpesviruses Type Varicella Zoster (Varicella zoster Virus (VZV))
  • Example 12 Efficacy in Influenza Virus B
  • Six cell culture dishes of type 1 cell culture according to Example 4 were infected with influenza virus B / Hong Kong / 5/72. 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium.
  • control group (3 cell culture dishes)
  • D2O the same amount of H2O was used instead of D2O for the dilution of the cell culture medium.
  • Example 4 Six cell culture dishes of type 1 cell culture according to Example 4 were infected with HSRV strain Long. 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium.
  • Example 15 Efficacy of Human Metapneumovirus A1 (HMPV)
  • Example 4 Six cell culture dishes of type 1 cell culture according to Example 4 were infected with HPMV type A1. 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium. The determination of the virus number according to Example 7 for Verum and control culture gave values which are shown in Table 1.
  • Example 17 Efficacy in Human Enterovirus Type EV71
  • Example 4 Six cell culture dishes of type 1 cell culture according to Example 4 were infected with human enterovirus type EV71, strain SHZH98. 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium. The determination of the virus number according to Example 7 for Verum and control culture gave values which are shown in Table 1.
  • Example 19 Preventive Efficacy in Herpesvirus Type 2 (Herpes Simplex Virus 2 (HSV-2))
  • Example 5 Six cell culture dishes of the modified type 1 cell culture of Example 5 were infected with herpesvirus type 2, strain 734, by American Type Culture Collection, Manassas, VA. 120 minutes after infection, the cell culture medium supplemented with the virus was removed and replaced with a diluted cell culture medium as follows: In the verum group (3 cell culture dishes) by 30% D2O and 70% DMEM with 10% FCS and 100 U / ml penicillin and 100 ⁇ g / ml streptomycin. In the control group (3 cell culture dishes), the same amount of H2O was used instead of D2O for the dilution of the cell culture medium.
  • the 28 subjects were randomized into 2 groups (verum group and control group) divided into 14 individuals each.
  • Each subject received a 20 g tube of a hydrogel prepared according to Example 2, the verum group a D2O hydrogel (made with 100% D2O), the control group an H2O hydrogel (made with 100% H2O) with the instruction, this immediately at first symptoms of aphthosis Apply Herpetica to the affected mucosal site and leave for 1 min.
  • the application should be repeated every 2 hours for a period of 3 days during the waking phases.
  • the maximum achieved size of the treated aphthae, the date and time of the first symptoms, the time of onset of therapy, the time of complete complete healing of the aphthae, the time of pain relief and the position of the aphthae should be indicated.
  • aphthae were considered, which were located in the mucosal area of the upper or lower lip, since these areas could be well observed by highlighting and measured by means of a test strip provided to the test persons in front of the mirror in their extent.
  • the selection criterion was an antibody titre of ⁇ 1: 2 with respect to the HRV strain used for the infection.
  • Another criterion for selection was non-smokers and the stated and credible readiness to refrain from smoking altogether during the experiment as well as no manifestation of diseases of the respiratory tract for at least 2 weeks prior to entry into the study. Exclusion criteria were: a) asthma and other chronic diseases of the respiratory tract, b) disorders of taste or smell perception, c) use of nasal sprays or other nasal applications within 2 weeks prior to entering the study, d) pregnancy.
  • the strain HRV 39 was used as HRV strain for infection of the test persons.
  • the strain was administered in the form of nasal drops to the subjects on day 0 of the study for inoculation with a virus concentration 200 times that of 50%.
  • Liquid phosphate-buffered saline, pH 7.0
  • HRV 39 was done per subject (100 ⁇ l per nostril and administration) 2 times within 20 minutes in a lying position as nasal drops.
  • the total duration of the study was 5 days, calculated from the time of HRV-39 infection.
  • subjects were randomized into 4 groups of 11 subjects: Verum Groups A and B and Control Groups C and D.
  • the groups differed in the primary and secondary endpoints of the study.
  • the primary measure of effectiveness was the reduction of the proportion of positive HRV-39 RNA; the smallest possible change in the average total symptom score (TSS) was the secondary measure of effectiveness.
  • TSS average total symptom score
  • the primary measure of effectiveness was a reduction of the mean TSS, which is composed of 6 Individual symptoms.
  • the secondary measure of effectiveness of the therapy groups was the reduction of the proportion of positive HRV-39 RNA.
  • the therapy group only test persons were evaluated in whom a successful infection by inoculation with HRV-39 could be detected. The criterion for this was a HRV-39-specific, serum-neutralized antibody titre increased by at least a factor of 4.
  • a nasal wash (“lavage" with 10 ml of phosphate buffered saline per nostril) was performed every 12 hours for all subjects and the effluent obtained was frozen for later RNA and virus titer analysis. Standard statistical methods were used to compare the summary symptom scores of the treatment groups on the individual test days, in particular variance and covariance analyzes.
  • the study medication was simply allied.
  • the protocol was as follows: For the prophylactic groups the administration of 200 ⁇ l per nasal opening was performed
  • Example 2 prepared nasal sprays (D20 for Verumen A and H2O for control group
  • Amounts as in prophylactic groups) of the nasal spray prepared according to Example 2 (D2O for Verum Group B and H2O for Control Group D) 2 hours after the HRV-39 infection and further every 2 hours during the awake periods as defined above until the end of the fourth
  • the total symptom score (TSS) used for the treatment and verum group consisted of 6 individual scores (runny nose, sore throat, malaise, nasal congestion, coughing, sneezing); each individual score was on a scale of 0 (very low) to 5 (very high) from the subject, based on the previously experienced maximum of the symptom in the previous evaluation.
  • the individual scores were recorded twice a day (early and evening) for each subject of the therapy groups. The 2 records received per day were then arithmetically averaged.
  • the first symptom score was recorded on day 0 immediately prior to HRV-39 infection.
  • HRV-39 RNA in the resulting nasal lavage samples was carried out according to standard methods by HRV-A TaqMan reverse-transcription PCR assay.
  • the serum neutralizing antibody titer to HRV-39 from the nasal lavage samples was determined by standard methods.
  • the selection criterion was a history of hyperactivity of the bronchial system to viral respiratory infections. Another criterion for selection was non-smoker or the stated and credible willingness to completely refrain from smoking during the experiment (duration 7 days) and no manifestation of respiratory tract illness for at least 2 weeks before entering the study. Other exclusion criteria were: a) asthma and other chronic diseases of the respiratory tract, b) disorders of taste or smell, c) pregnancy.
  • the strain Long was used as HSRV strain for infection of the test persons.
  • the strain was administered to subjects for aerosol inoculation on Day 0 of the study at a virus concentration equivalent to 200 times the 50% tissue infectious tissue culture concentration (TCID 50 ) and in 200 ⁇ l of liquid (phosphate-buffered Saline, pH 7.0) was dissolved.
  • HRSV was administered on day 0 of the study by two sprays with a hand-held nebulizer into the throat of the subjects during inhalation. The time between the two sprays was 20 min., About 90-110 ⁇ l of liquid were sprayed per shot. Only those subjects were admitted for therapy, at least 24 hours after inoculation dry cough occurred and where pneumonia could be excluded as a cause.
  • the total duration of the study was 7 days, calculated from the time of HRSV infection. Immediately prior to infection, subjects were randomized into 2 groups of 9 subjects: verum group and control group.
  • the primary endpoint of the study was defined by the prevalent specificity of HRSV for lower respiratory tract involvement, in particular the induction of acute bronchitis. This is associated with a measurable obstruction of the respiratory tract, which can be quantified by lung function diagnostics (spirometer). As baseline value, a spirometer reading was taken just prior to HRSV infection. Therefore, the primary goal of the study was the sustained reduction of spirometrically quantified airway obstruction as a result of HRSV infection.
  • a nasal wash (“lavage" with 10 ml of phosphate buffered saline per nostril) was performed every 24 hours for all subjects and the effluent obtained was frozen for later RNA and virus titer analysis.
  • the study medication was simply allied.
  • the protocol was as follows: The administration of 10 ml each of the isotonic NaCl solution prepared according to Example 2 was carried out 3 times daily for the two groups in the form of an aerosol prepared according to Example 3.
  • the verum group received consistently D2O, the control group consistently H2O aerosol.
  • the end of the medication was the evening of the 6th study day.
  • the lower airway obstruction was measured twice a day by means of a spirometer type Vitalograph 2120 according to the manufacturer (Vitalograph Ltd. D Maids Moreton, Buckingham MK18 1SW, England) in FVC mode ("Forced Vital Capacity") Spirotrac IV software of the device.
  • the measured variables were the "Forced Vital Volume” after 1 second exhalation (FEV1) and the "Forced Vital Capacity” (FVC), from these two variables the ratio FEV1 / FVC was calculated in percent and as a characteristic variable for the description of HRSV. Bronchitis caused obstruction of the airways.
  • the quantification of the HRSV RNA in the nasal lavage samples obtained on days 0-7 was carried out according to standard methods by reverse-transcription PCR assay.
  • the determination of the antibody titer to HRSV from the nasal lavage samples was carried out by using an anti-HRSV antibody by ELISA.

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Abstract

L'invention concerne l'utilisation d'oxyde de deutérium pour la prophylaxie et/ou la thérapie d'affections virales des voies respiratoires.
EP10701904.4A 2009-01-07 2010-01-06 Utilisation d'oxyde de deutérium pour le traitement d'affections virales des voies respiratoires Not-in-force EP2385834B1 (fr)

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DE102009003992A DE102009003992A1 (de) 2009-01-07 2009-01-07 Verwendung von Deuteriumoxid zur Behandlung Virus-basierter Erkrankungen des Respirationstraktes
PCT/IB2010/000028 WO2010079420A1 (fr) 2009-01-07 2010-01-06 Utilisation d'oxyde de deutérium pour le traitement d'affections virales des voies respiratoires

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WO2010079420A1 (fr) 2010-07-15
EP2385834B1 (fr) 2015-12-16
CN102369012B (zh) 2015-06-10
CN102369012A (zh) 2012-03-07

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